Prostate cancer is the most common cancer in men and the number of new cases is increasing. For example in US this prostate cancer affects approximately 230000 patients per year. However, in most cases, the cancer is a slowly developing disease and the 5-year survival is about 90%. There are several treatment options with different impact on patient quality of life. The decision and management processes of prostate cancer treatment are complex and involve a delicate balance between optimization of clinical benefits, life expectancy and minimization of treatment-related side-effects.
In total approximately four out of 10 cancer patients receive radiotherapy as part of their treatment. The damage of normal tissue leads to acute side-effects that often turn into chronic problems.
Basic treatment options for prostate cancer are watchful waiting, radical prostatectomy, and radiotherapy. Radiation as first line treatment is applied in about 50% of all prostate cancer cases. Recurrent disease is almost completely treated with radiotherapy. Radiation is delivered in several fractions, most often daily over a period of several weeks, e.g. 76 Gy in 38 fractions over 8 weeks. Radiotherapeutic treatment options include external beam therapy (EBT), e.g. conformal radiation therapy where the radiation is delivered to the diseased area while attempting to spare surrounding tissue. Radiation therapy procedures include 3D conformal radiation therapy and intensity modulated radiation therapy (IMRT). An alternative to EBT is brachytherapy, which uses seeds of radioactive isotopes that are temporary or permanently implanted into the prostate. Temporary implantation is done with high dose rate (HDR) sources, e.g. Ir-192, often in combination with EBT. Permanent implantation uses low dose rate (LDR) seeds, e.g. Pd-103. In general, brachytherapy results in a lower dose to surrounding healthy tissue and risk organs, giving less severe side-effects of the radiation treatment.
Radiotherapy plays an important role in other cancer types as well. In the developed countries, 80% of lung cancer patients, 75% of breast cancer patients, and all head and neck cancers are treated with radiation therapy.
The maximum radiation dose that can be given is limited by the tolerance of normal tissues within the radiation field. The radiation response varies considerably between individuals and the tolerance of the most sensitive subjects limits the dose that can be given to the population as a whole, which may limit the chance of tumor cure. Ionizing radiation induces orchestrated response cascades at cellular as well as tissue level. The responses involve differential regulation of several cytokine cascades, which together impact the resulting normal tissue damage. Radiation-induced damage of normal tissue involves many different cell types and the long-term tissue composition is likely to change as a result of radiation. For example, the amount of inflammatory cells and fibrotic tissue increases after irradiation.
Genetic microarrays have been used for radiotoxicity prognosis, i.e. to generate gene signatures identifying radiotoxicity sensitive and resistant populations. Furthermore, microarray techniques have also been employed for mechanistic purposes, i.e. to identify genes and pathways involved in tissue injury response. In interpretation of microarray results, care has to be taken. The methodology is still immature for clinical routine use. Inconsistencies between different microarray platforms make it almost impossible to compare independently obtained data sets addressing the same biological problem. Also, probe sequence information was until now most often not provided for commercially available microarrays. It has been shown that genetic changes from radiotherapy can be detected in peripheral blood cells (circulating lymphocytes) and that these changes correlate with development of acute toxicity. Also, gene expression profiles for in vitro irradiated lymphocytes correlate with acute or late radiation injury.
Before radiation treatment of prostate cancer starts, the patient is normally imaged using various techniques. Needle biopsies are most often taken under transrectal ultrasound (TRUS) guidance. However, the TRUS image contrast is not high enough for detection of early-stage prostate cancer. For staging of more advanced prostate cancer, anatomical imaging modalities like x-ray computed tomography (CT) and magnetic resonance imaging (MRI) can be used, e.g. to detect extra-capsular tumor extensions, seminal vesicle involvement, and abnormal sizes of lymph nodes. Functional imaging modalities can also be employed, e.g. positron-emission tomography (PET) using choline tracers, single-photon emission computed tomography (SPECT), and special MR schemes (MR spectroscopy, Combidex® for lymph-node staging). Finally, for planning and simulation of the radiotherapy, a planning CT scan is made, tumor and sensitive organs are outlined on axial slices, and the geometric centre of the tumor volume is calculated.
Local control of a tumor increases with the administered radiation dose. However, by increasing the radiation dose, the risk of complications increases. In the case of prostate cancer, the primary risk organs and structures are bladder, urethra, rectum, seminal vesicles and associated nerve bundles controlling sexual function. The incidence of complications is also associated with the size of the irradiated volume. There are several ways to assess such so-called radiation toxicity. These include physician-reported instruments, e.g. the RTOG acute and late toxicity questionnaires, EORTC, the Royal Marsden Scale that measures symptom frequency, and the LENT/SOM questionnaires. Additionally, there are patient-reported quality of life questionnaires like MOS SF-36, UCLA Prostate Cancer Index, the expanded prostate cancer index composite (EPIC), and FACT-P.
There are several predictors of radiation toxicity. For example, the mean rectal dose correlates with acute rectal and intestinal toxicity in 3D conformal radiotherapy of prostate cancer, whereas hormonal therapy and the use of anticoagulants are protective. More precisely, a larger mean rectal dose is associated with a larger bleeding risk, larger irradiated volumes are associated with stool frequency, tenesmus, incontinence, and bleeding. Hormonal therapy is protective against frequency and tenesmus; hemorrhoids are associated with a larger risk of tenesmus and bleeding, and diabetes associate with diarrhea. The dose to the rectal wall can be analyzed in more detail by use of dose-volume histograms (DVH) from 3D treatment planning systems. By such analysis, the volume of rectal wall receiving the highest dose (e.g. the wall volume receiving >70Gy), the irradiated rectum area, target and rectum size may in some cases be more predictive of late rectal toxicity than the mean rectal dose. Target volume and height, rectum surface area and average cross-sectional area have also been shown to correlate with toxicity. The bladder volume and the percentage of the bladder volume that receives 10-90% of the prescribed dose are correlated with urinary function and patient questionnaire bother scores. Furthermore, a full bladder improves the position consistency of the prostate and lowers the bladder and bowel doses.
The prostate is situated between the bladder and the rectum, both radiosensitive organs. During radiotherapy, most prostate cancer patients develop acute side-effects from radiation damage in surrounding organs, e.g. diarrhea, rectal bleeding, abdominal cramps, tenesmus, impotence, fecal or urinary incontinence. According to a recent study, approximately 80% of patients receiving pelvic radiotherapy developed gastrointestinal problems. In some patients, radio-damage of normal tissue even leads to chronic gastrointestinal problems or impotence. Obviously, both acute and late radiotoxicity effects have severe impact on patients' quality of life. Furthermore, very severe acute side-effects may lead to discontinuance of radiotherapy, resulting in impaired tumor control.
Therapy monitoring and individual therapy adjustment are important issues. As described, individuals are significantly affected by impaired quality-of-life and limited tumor control. Regarding healthcare costs, acute and especially chronic side-effects due to radiation damage require considerable treatment. Hence, reducing (or even avoiding) side-effects early in the cancer treatment may save expenditures on side-effect treatment.
Thus, there is a need for a method and a device for monitoring side-effects of radiation treatment.
The present inventors have realized that there is no single biomarker of side-effects and radiotoxicity. Therefore an idea is to utilize information provided by multiple biomarkers jointly.
A general idea of the present invention is to combine parameters obtained from morphology, from metabolic, functional, physiological, or pharmacological characteristics and therapy parameters, and subsequently evaluate and/or prognosticate disease status including side-effects. The resulting information may be used to adapt therapy.
Moreover, an idea is to process a combination of medical imaging features with in vitro diagnostics (IVD) data in order to calculate an output signal being indicative of the radiotoxicity in an area of the tissue of interest. Particularly advantageous is the combination of image-derived features with information provided by molecular biomarkers, information on concomitant medication, and anamnesis.
An object is to provide a method for therapy monitoring, particularly for diagnosing radiotoxicity and adapting radiotherapy depending on the level of radiotoxicity.
Another object is to provide a method, which combines the information provided by imaging with the information provided by molecular biomarkers to deduce a measure of radiotoxicity for treatment adjustment and optimization.
Moreover, data from a patient questionnaire may be utilized in deducing the measure of radiotoxicity.
According to an aspect a method for radiotherapy monitoring is provided. The method comprises obtaining at least one image derived descriptor from an image modality, wherein the image derived descriptor pertains to a tissue of interest for which radiotherapy is planned or a tissue in the vicinity of this target volume. The method further comprises selecting at least one disease specific biomarker suitable for detecting or quantifying radiotherapy side-effects in the area of the tissue of interest. Furthermore, the method comprises retrieving at least one measurement value of the selected disease specific in vitro diagnostic biomarker. Moreover, the method comprises processing the at least one image derived descriptor and the at least one disease specific in vitro diagnostic biomarker measurement value by means of a correlation technique, resulting in an output signal indicative of the radiotoxicity in the area of the tissue of interest.
The method according to some embodiments takes into account a set of parameters, such as the size of tumor target and genetic profiles, which have prognostic value. The analysis of such parameters allows for estimating the risk to develop side-effects for a given treatment, in particular for radiotherapy. Hence, the method may also be utilized as prognostic tool in treatment decisions even before radiation treatment is actually employed or started.
The method provides for optimized radiotherapy planning, early detection of radiotoxicity and concomitant dose adjustment which may help minimizing complications while keeping target dose as high as possible. In particular, side-effect preventive measures may be taken at an early point in time during radiotherapy.
In another aspect a computer program product is provided, wherein the computer program product having embodied thereon a computer program for processing by a data-processing apparatus. The computer program comprises a first code segment for obtaining at least one image-derived descriptor from an image modality, wherein the image derived descriptor pertains to a tissue of interest for which radiotherapy is planned. The computer program further comprises a second code segment for selecting at least one disease specific biomarker suitable for detecting or quantifying radiotherapy side-effects in the area of the tissue of interest. Moreover, the computer program comprises a third code segment for retrieving at least one measurement value of the selected disease specific in vitro diagnostic biomarker. Furthermore, the computer program comprises a fourth code segment for processing the at least one image derived descriptor and the at least one disease specific in vitro diagnostic biomarker measurement value by means of a correlation technique, resulting in an output signal indicative of the radiotoxicity in the area of the tissue of interest.
According to another aspect a method for producing an individual patient profile is provided. The method comprises inputting data comprising individual patient answers to multiple-choice questions of a medical questionnaire. Moreover, the method comprises storing the answers forming an individual patient profile comprising the answer selection excluding the actual question text. The method further comprises storing information of the questionnaire version presented to the patient and the date of questionnaire completion in the data file. Furthermore, the method comprises creating an individual patient profile report by applying a profile processing algorithm on the information of the data file, such as at least one of the answers. The method further comprises displaying the individual patient profile report on a display device.